Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo‐M ratio as an index of efficacy at cortical muscarinic receptors

Abstract

Radioligand binding assays using [3H]‐N‐methylscopolamine (NMS) and [3H]‐oxotremorine M (Oxo‐M) have been devised to predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex. Muscarinic antagonists, including non‐selective and both M1‐ and M2‐selective compounds, displayed similar affinity for both binding assays. Full agonists such as carbachol and muscarine possessed a ratio of potencies against the antagonist versus the agonist ligand (NMS/Oxo‐M ratio) of > 4000. Compounds which have been shown previously to display partial agonist activity in functional assays e.g. pilocarpine and RS86 had intermediate NMS/Oxo‐M ratios of 100–150. A second group of compounds which included oxotremorine had somewhat higher ratios (500–1400). The ratio of affinity constants for the two assays predicted the ability of agonists to stimulate cortical phosphatidyl‐inositol turnover. These results suggest that the NMS/Oxo‐M ratio may be a useful prediction of efficacy for novel compounds acting at cortical muscarinic receptors. 1988 British Pharmacological Society